Chemical derivatives and their application as antitelomerase agents

ABSTRACT

The present invention relates to cancer therapy and to novel anticancer agents having a mechanism of action which inhibits telomerase. It also relates to novel chemical compounds as well as their therapeutic application in humans.

[0001] This application claims the benefit of priority from FrenchApplication No. 0100205, filed Jan. 9, 2001, and U.S. ProvisionalApplication No. 60/270,164, filed Feb. 22, 2001, which are bothincorporated herein by reference in their entirety.

[0002] The present invention relates to cancer therapy and to novelanticancer agents having a mechanism of action which is quite specific.It also relates to novel chemical compounds as well as their therapeuticapplication in humans.

[0003] The present invention relates to the use of novel non-nucleotidechemical compounds which interact with specific structures ofdeoxyribonucleic acid (DNA). These novel compounds consist of adistribution agent linked to an aminoaromatic group. These novelcompounds are useful in the treatment of cancers and typically act astelomerase-inhibiting agents. They are also useful for stabilizing DNAin G-quadruplex structures (e.g., guanine tetrads). The inhibition oftelomerase via the stabilization of these G-quadruplexes generallyresults in the termination of cellular mitosis and the death ofrapidly-dividing cells such as cancer cells. It may also result in theinduction of senescence in cancer cells. Thus, such telomeraseinhibiting agents have important therapeutic applications.

[0004] The compounds of the present invention have the advantage, fromthe therapeutic point of view, of blocking telomerase. From a biologicalpoint of view, telomerase allows the addition of repetitive DNAsequences of the T T A G G G type (termed telomeric sequences) to theend of the telomere during cell division. Through this action,telomerase renders the cell immortal. Indeed, in the absence of thisenzymatic activity, the cell loses 100 to 150 bases at each division,which rapidly renders it senescent. During the development ofrapidly-dividing cancer cells, these cells were found to possesstelomeres which were maintained at a stable length during cell division.In these cancer cells, telomerase was found to be highly activated andallowed the addition of repetitive motifs of telomeric sequences at theend of the telomere. This allowed conservation of the length of thetelomeres in the cancer cells. During the past few years, more than 85%of cancer cells have tested positive for the presence of telomerase,whereas somatic cells do not show this characteristic.

[0005] Thus, telomerase is an important target for treating cancercells. The first approach for blocking telomerase was the use ofnucleotide structures (Chen et al., Proc. Natl. Acad. Sci. USA 93(7),2635-2639). Diaminoanthraquinones (Sun et al., J. Med. Chem. 40(14),2113-6) and diethyloxadicarbo-cyanins (Wheelhouse R. T. et al., J. Am.Chem. Soc. 120:3261-2, 1998) are among the non-nucleotide compoundswhich have been used.

[0006] Patent WO 99/40087 describes the use of compounds which interactwith the G-quadruplex structures. Such G-quadruplex structures aretypically perylene compounds and carbocyanins containing at least sevenrings, including two heterocycles.

[0007] It has been discovered, quite surprisingly, that simplestructures could achieve a result which is at least equivalent withstructures which are a lot less complicated from a chemical point ofview. The compounds of the present invention which meet the intendedobjective, i.e., which bind the G-quadruplex structure and therebyexhibit a telomerase-inhibiting activity, correspond to the followinggeneral formula:

[0008] nitrogen-containing aromatic ring —NR₃— distribution agent —NR′₃—nonaromatic hydrocarbon chain

[0009] in which

[0010] the nitrogen-containing aromatic ring represents:

[0011] a quinoline optionally substituted with at least

[0012] a group N(Ra)(Rb) in which Ra and Rb, which are identical ordifferent, represent hydrogen or a C1-C4 alkyl radical or

[0013] a group ORa in which Ra is as defined above

[0014] a quinoline possessing a nitrogen atom in quaternary form or

[0015] a benzamidine or

[0016] a pyridine

[0017] R3 and R′3, which are identical or different, representindependently of each other hydrogen or a C1-C4 alkyl radical

[0018] the distribution agent represents:

[0019] a triazine group optionally substituted with an alkyl radicalhaving 1 to 4 carbon atoms, a thio, oxy or amino radical which arethemselves optionally substituted with one or more short-chain alkylchains containing 1 to 4 carbon atoms or alternatively a halogen atom or

[0020] a carbonyl group or

[0021] a group C(═NH)—NH—C(═NH) or

[0022] an alkyldiyl group containing 3 to 7 carbon atoms or

[0023] a diazine group optionally substituted with the same groups astriazine

[0024] or one of its salts.

[0025] For the purposes of the above formula, nonaromatic hydrocarbonchain is understood to mean an alkyl (C1-C4) or alkenyl (C2-C4) chain,which is linear or branched, or a cycloalkyl (C3-C18), cycloalkenyl(C3-C18) or heterocycloalkyl (C3-C18) chain. The heterocycloalkyl groupoptionally includes the nitrogen atom.

[0026] It is of course understood that the nonaromatic hydrocarbon chainmay be optionally substituted with one or more atoms or radicals chosenfrom among halogen atoms, hydroxyl, aryl, heteroaryl, alkyloxy, aryloxy,thio, alkylthio, arylthio, amino, alkylamino and/or arylamino,dialkylamino, diarylamino, amidino, guanidino, alkylcarbonylamino,arylcarbonylamino, carboxyl, alkyloxycarbonyl, aryloxycarbonyl,aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,dialkylaminocarbonyl, alkylcarbonyl, arylcarbonyl, cyano,trifluoromethyl, and combinations thereof.

[0027] The alkyl chains of the optional substituents of the hydrocarbonchain may contain 1 to 4 carbon atoms; and the aryl groups of theoptional substituents of the hydrocarbon chain may contain 5 to 18carbon atoms.

[0028] In one embodiment, the compounds include a distribution agentchosen from a triazine and a diazine group. Suitable diazine groupsinclude pyrimidines and quinazolines. The hydrocarbon chains may bealkyl chains containing 2 to 3 carbon atoms; and the heterocycloalkyl orcycloalkyl chains may contain 4 to 7 carbon atoms.

[0029] Suitable triazines include the compounds corresponding to formula(I) below:

[0030] in which:

[0031] A represents

[0032] an amino group of formula NR1R2 in which R1 and R2, which areidentical or different, represent hydrogen or a straight or branchedalkyl group containing 1 to 4 carbon atoms or

[0033] a group OR1 or SR1 in which R1 has the same meaning as above or

[0034] an alkyl group containing 1 to 4 carbon atoms or atrifluoromethyl group or

[0035] a hydrogen atom or

[0036] a halogen atom chosen from fluorine, chlorine, bromine, andiodine

[0037] R3 and R′3, which are identical or different, representindependently of each other hydrogen or a C1-C4 alkyl radical,

[0038] Ar1 represents:

[0039] a nitrogen-containing aromatic ring representing:

[0040] a quinoline optionally substituted with at least

[0041] a group N(Ra)(Rb) in which Ra and Rb, which are identical ordifferent, represent hydrogen or a C1-C4 alkyl radical or

[0042] a group ORa in which Ra is as defined above

[0043] a quinoline possessing a nitrogen atom in quaternary form or

[0044] a benzamidine or

[0045] a pyridine attached at the 4-position or fused with an aryl orheteroaryl group optionally substituted with a C1-C4 alkyl group

[0046] alk represents

[0047] an alkyl unit containing 2 to 3 linear or branched carbon atomssubstituted with an amino, alkylamino, arylamino, dialkylamino,diarylamino, or combination thereof

[0048] an alkenyl unit containing 2 to 3 carbon atoms substituted withan amino, alkylamino, arylamino, dialkylamino, diarylamino, orcombination thereof

[0049] a heterocyclyl unit containing from 4 to 7 carbon atoms

[0050] or one of its salts.

[0051] It is evident that the quinoline motifs may be substituted by anyother group not involved in the intended application; thus, acridine,isoquinoline, quinazoline, quinoxaline, phthalazine, benzothiazine,benzoxazine, phenoxazine, and phenothiazine groups are included in thedefinition of the quinoline groups.

[0052] In one embodiment, compounds of formula (I) include thosecomprising a heterocycle chosen from the 4-aminoquinolyl, 4-alkyl- and4-dialkyl-aminoquinolyl, 4-aminoquinolinium and quinolinium groups inwhich the quinolinium ring is optionally substituted with a methylgroup.

[0053] Group A may represent methylthio, amino, alkylamino ordialkylamino radical, in which the alkyl groups in the radicals possess1 to 4 carbon atoms.

[0054] The nonaromatic hydrocarbon chain may represent a2-(dialkylamino)ethyl, 3-(dialkylamino)propyl,2-(N-alkyl-N-arylamino)ethyl, or 3-(N-alkyl-N-arylamino)propyl chain inwhich the alkyl groups may contain 1 to 4 carbon atoms or, in analternative embodiment, 1 to 2 carbon atoms; and the aryl groups maycontain 5 to 18 carbon atoms or, in an alternative embodiment, 6 carbonatoms.

[0055] Another subject of the present invention relates to the compoundsof formula (I) as novel chemical products. It therefore relates to thenovel products corresponding to the following formula (I):

[0056] in which:

[0057] A represents

[0058] an amino group of formula NR1R2 in which R1 and R2, which areidentical or different, represent a straight or branched alkyl groupcontaining 1 to 4 carbon atoms or

[0059] a group OR1 or SR1 in which R1 represents hydrogen or has thesame meaning as above or

[0060] an alkyl group containing 1 to 4 carbon atoms or atrifluoromethyl group or

[0061] a hydrogen atom or

[0062] a halogen atom chosen from fluorine, chlorine, bromine, andiodine

[0063] R₃ and R′₃, which are identical or different, representindependently of each other a hydrogen atom or a C1-C4 alkyl group,

[0064] Ar₁ represents:

[0065] a nitrogen-containing aromatic ring representing:

[0066] a quinoline optionally substituted with at least

[0067] a group N(Ra)(Rb) in which Ra and Rb, which are identical ordifferent, represent hydrogen or a C1-C4 alkyl radical or

[0068] a group ORa in which Ra is as defined above

[0069] quinoline possessing a nitrogen atom in quaternary form or

[0070] a benzamidine or

[0071] a pyridine attached at the 4-position or fused with an aryl orheteroaryl group optionally substituted with a C1-C4 alkyl group

[0072] alk represents

[0073] an alkyl unit containing 2 to 3 linear or branched carbon atomssubstituted with an amino, alkylamino, arylamino, dialkylamino,diarylamino, or combination thereof

[0074] an alkenyl unit containing 2 to 3 carbon atoms substituted withan amino, alkylamino, arylamino, dialkylamino, diarylamino, orcombination thereof

[0075] a heterocyclyl unit containing from 5 to 7 carbon atoms

[0076] or one of its salts.

[0077] In one embodiment, Ar₁ represents a group chosen from among4-amino-, 4-methylamino- and 4-dimethylamino-quinolyl and quinolyniumgroups, in which the quinolinium nucleus is optionally substituted witha methyl group.

[0078] The A group may represent an amino or dimethylamino or methylthiogroup.

[0079] The compounds of general formula (I) include those for which thenonaromatic hydrocarbon chain may represent a 2-(dialkylamino)ethyl,3-(dialkylamino)propyl, 2-(N-alkyl-N-arylamino)ethyl or3-(N-alkyl-N-arylamino)propyl chain in which the alkyl groups contain 1to 4 carbon atoms, or 1 to 2 carbon atoms; and the aryl groups contain 5to 18 carbon atoms or 6 carbon atoms.

[0080] For example, the nonaromatic hydrocarbon chain may represent a2-(N-m.tolyl-N-ethylamino)ethyl chain.

[0081] Another subject of the present invention relates to the use ofthe compounds of formula (I) as pharmaceutical products for human use.

[0082] The methods of preparing the compounds of formula (I)

[0083] are described below.

[0084] In the case where Ar₁ and Alk are present, the triazine ofgeneral formula (A) may be obtained by sequential displacement of thehalogen atoms, most generally of chlorine atoms, from the products ofgeneral formula (B), by the amines Ar₁ and then Alk of general formula(C), according to scheme 1:

[0085] Generally, the procedure is carried out with 1 mole ofdihalo-s-triazine, or trihalo-s-triazine, and 1 mole of amine Ar₁. Theprocedure is typically carried out in an inert solvent, such as acetone,which is optionally aqueous; or an alcohol which is optionally aqueous,such as ethanol; or a halogenated solvent, such as dichloromethane; oran ether, such as diethyl ether or dioxane; or a polar aprotic solvent,such as DMF, DMSO or NMP. In one embodiment, the procedure is carriedout at a temperature of between 20° C. and 50° C. Next, 1 mole of amineAlk is added to the product of general formula (D), which may beoptionally isolated. The procedure is generally carried out at atemperature of between 50° C. and the reflux temperature.

[0086] It is also possible to carry out the procedure under theconditions described in J. Fluor. Chem., 1988, 39(1), 117-123, which isherein incorporated by reference.

[0087] General Method 2

[0088] According to a second method, the products of general formula (A)in which Ar are as defined above and R represents a group NR1R2 or OR1or SR1 may also be prepared by nucleophilic displacement of a halogenatom, generally a chlorine atom, from a product of general formula (A)in which R represents a halogen atom. This second method is performedaccording to scheme 2:

[0089] The procedure is generally carried out by condensing 1 mole ofproduct of general formula (A) in which R represents a halogen atom,preferably a chlorine atom, with 1 mole of amine R1R2NH or alcoholateRiO⁻ or thioalcoholate R1S. The reaction takes place in an inert mediumunder the reaction conditions. There may be mentioned among the inertsolvents acetone, which is optionally aqueous; or an alcohol, which isoptionally aqueous such as ethanol; or a halogenated solvent, such asdichloromethane; or an ether, such as diethyl ether or dioxane; or apolar aprotic solvent, such as DMF, DMSO or NMP. When the entering groupis a R1R2NH group, the procedure is typically carried out at atemperature of between 20° C. and the reflux temperature, in thepresence of an organic base such as triethylamine, or an inorganic basesuch as sodium hydroxide or sodium or potassium carbonate. It is alsopossible not to use a base during the amination reaction, and to isolatea hydrochloride of the product of general formula (A), the base of whichcan then be released. When the entering group represents a RiO⁻ or R1S⁻group, the procedure is typically carried out with an alkali metal oralkaline-earth metal alcoholate or thioalcoholate, such as a sodium orpotassium or lithium or ammonium or cesium or barium salt, in a polaraprotic solvent such as DMF or DMSO or NMP, at a temperature of between50° C. and the reflux temperature.

[0090] General Method 3

[0091] According to a third method of preparing the compounds, for whichR represents a hydrogen atom or a straight or branched alkyl groupcontaining from 1 to 4 carbon atoms, the compounds may be prepared bycondensation of a bisguanide of general formula (E), with an acidderivative, such as an acid chloride or a methyl ester of generalformula (F) according to scheme 3:

[0092] The condensation between the bisguanide of general formula (E)and the acid derivative of general formula (F) is generally carried outin an alcohol such as methanol or ethanol. The procedure is typicallycarried out at a temperature of between 0° C. and the refluxtemperature.

[0093] The symmetric or asymmetric bisguanides of general formula (E)may be obtained by carrying out the procedure under the conditionsdescribed in the literature, for example, according to Patent J.P.94-4993.

[0094] General Method 4

[0095] It is understood that the s-triazines, in general, may beobtained in the form of libraries, by applying the methods described inschemes 1, 2, or 3 in parallel and/or combinatorial chemistry in liquidphase or in solid phase. It is generally understood that when the workis carried out in solid phase, any one of the reagents may be attachedbeforehand onto a solid support, chosen according to the chemicalreaction involved, and that such a chemical reaction is followed by anoperation of cleaving the product of the reaction from the solidsupport.

[0096] The present invention also relates to therapeutic compositionscontaining a compound according to the invention, in combination with apharmaceutically acceptable carrier. Such a carrier is typically chosenin accordance with the desired mode of administration. Thepharmaceutical composition may be provided in solid, liquid or liposomeform.

[0097] Suitable solid compositions include powders, gelatin capsules,and tablets. Among the oral forms, it is also possible to provide solidforms which are protected from the acidic medium of the stomach. Thecarriers used for the solid forms may comprise inorganic carriers suchas phosphates, carbonates, or organic carriers such as lactose,celluloses, starch or polymers. The liquid forms may comprise solutions,suspensions or dispersions. They may also contain, as a dispersivecarrier, either water, or an organic solvent (ethanol, NMP and thelike), or mixtures of surfactants and solvents, or mixtures ofcomplexing agents and solvents.

[0098] The administered dose of the compounds of the invention will beadjusted by the practitioner according to the route of administration tothe patient and the condition of the patient.

[0099] The compounds of the present invention may be administered aloneor mixed with other anticancer agents. Suitable agents include, but arenot limited to:

[0100] alkylating agents such as cyclophosphamide, melphalan,ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine,lomustine, semustine, steptozotocin, decarbazine, temozolomide,procarbazine and hexamethylmelamine

[0101] platinum derivatives such as cisplatin, carboplatin oroxaliplatin

[0102] antibiotic agents such as bleomycin, mitomycin, dactinomycin,

[0103] antimicrotubule agents such as vinblastine, vincristine,vindesine, vinorelbine, taxoids (paclitaxel and docetaxel)

[0104] anthracyclines such as doxorubicin, daunorubicin, idarubicin,epirubicin, mitoxantrone, losoxantrone

[0105] group I and II topoisomerases such as etoposide, teniposide,amsacrine, irinotecan, topotecan and tomudex,

[0106] fluoropyrimidines such as 5-fluorouracil, UFT, floxuridine,

[0107] cytidine analogs such as 5-azacytidine, cytarabine, gemcitabine,6-mercaptomurine, 6-thioguanine

[0108] adenosine analogs such as pentostatin, cytarabine or fludarabinephosphate

[0109] methotrexate and folinic acid

[0110] enzymes and various compounds such as L-asparaginase,hydroxyurea, trans-retinoic acid, suramine, dexrazoxane, amifostine,herceptin as well as estrogenic and androgenic hormones.

[0111] It is also possible to combine a radiation treatment with thecompounds of the present invention. These treatments may be administeredsimultaneously, separately or sequentially. The treatment is typicallyadapted by the practitioner to the patient to be treated.

[0112] The G-quadruplex stabilizing activity may be determined by amethod using the formation of a complex with fluorescein, as describedbelow.

[0113] Oligonucleotides

[0114] All the oligonucleotides, modified or otherwise, were synthesizedby Eurogentec SA, Seraing, Belgium. The oligonucleotide FAM+DABCYLcarries the catalog reference OL-0371-0802. It has the sequence:GGGTTAGGGTTAGGGTTAGGG (SEQ ID NO:1) corresponding to 3.5 repeats of thehuman telomeric motif (strand rich in G). The fluorescein is chemicallyattached to the 5′ end, and the DABCYL to the 3′ end, as described byEurogentec. The concentration of the samples is checked byspectrophotometry, recording the absorbance spectrum between 220 and 700nm and using the molar extinction coefficient provided by the supplier.

[0115] Buffers

[0116] All the experiments were carried out in a 10 mM sodium cacodylatebuffer pH 7.6 containing 0.1 M Lithium Chloride (or Sodium Chloride).The absence of fluorescent contamination in the buffer was checkedbeforehand. The fluorescent oligonucleotide is added at the finalconcentration of 0.2 μM.

[0117] Study of Fluorescence

[0118] All the measurements of fluorescence were carried out on a SpexFluorolog DM1B apparatus, using an excitation line width of 1.8 nm andan emission line width of 4.5 nm. The samples are placed in amicroquartz cuvette of 0.2×1 cm. The temperature of the sample iscontrolled by an external water bath. The oligonucleotide alone wasanalyzed at 20, 30, 40, 50, 60, 70 and 80° C. The emission spectra arerecorded using an excitation wavelength of 470 nm. The excitationspectra are recorded using either 515 nm or 588 nm as emissionwavelength. The spectra are corrected for the response of the instrumentby reference curves. A high extinction (80-90%) of the fluorescence offluorescein at room temperature is observed, in agreement with anintramolecular folding of the oligonucleotide at 20° C. in the form of aG-quadruplex. Such folding induces juxtaposition of the 5′ and 3′ endsof the oligonucleotide, which are respectively linked to fluorescein andto DABCYL. This juxtaposition causes an already-described phenomenon ofextinction of fluorescence which is used for “Molecular Beacons”.

[0119] Fluorescence Tm:

[0120] An oligonucleotide stock solution at the strand concentration of0.2 μM in 0.1 M LiCl, 10 mM cacodylate buffer, pH 7.6, is preparedbeforehand, heated briefly at 90° C. and slowly cooled to 20° C., andthen distributed in aliquots of 600 μl in the fluorescence cuvettes.Three μl of water (for the control) or 3 μl of test product (stock at200 μM, final concentration 1 μM) are then added and mixed. The samplesare then allowed to incubate for at least 1 hour at 20° C. before eachmeasurement. The use of longer incubation times (up to 24 hours) has noinfluence on the result obtained.

[0121] Each experiment allows the measurement of only one sample. Thelatter is first incubated at an initial temperature of 20° C., heated to80° C. over 38 minutes, left for 5 minutes at 80° C. and then cooled to20° C. over 62 minutes. During this time, the fluorescence is measuredsimultaneously at two emission wavelengths (515 nm and 588 nm) using 470nm as the excitation wavelength. A measurement is carried out every 30seconds. The temperature of the water bath is recorded in parallel. Thefluorescence profile as a function of the temperature is reconstitutedfrom these values. The fluorescence profiles are then normalized between20° C. and 80° C. The temperature for which the intensity of emission at515 nm is the mean of those at high and low temperature is called theTm. Under these conditions, the Tm of the reference sample withoutaddition of product is 44° C. in a Lithium Chloride buffer. Thistemperature is increased to more than 55° C. in a Sodium Chloridebuffer. The addition of a G-quadruplex stabilizing compound induces anincrease in the Tm. This increase is judged to be significant if it isgreater than 3°.

[0122] The antitelomerase biological activity is determined by thefollowing experimental protocol:

[0123] Preparation of the Extract Enriched in Human Telomerase Activity:

[0124] The leukemia line HL60 is obtained from ATCC (American TypeCulture Collection, Rockville USA). The cells are cultured in suspensionin RPMI 1640 medium containing L-Glutamine at 2 mM, Penicillin 200 U/ml,streptomycin 200 μg/ml, gentamycin 50 μg/ml and supplemented with 10%heat-inactivated fetal calf serum.

[0125] An aliquot of 10⁵ cells is centrifuged at 3000×G and thesupernatant discarded. The cell pellet is resuspended by severalsuccessive pipettings in 200 μl of lysis buffer containing 0.5% CHAPS,10 mM Tris-HCl pH 7.5, 1 mM MgCl₂, 1 mM EGTA, 5 mM β-mercaptoethanol,0.1 mM PMSF and 10% glycerol and is stored in ice for 30 minutes. Thelysate is centrifuged at 16 0000×G for 20 minutes at 4° C., and 160 μlof supernatant is recovered. The proteins in the extract are assayed bythe Bradford method. The extract is stored at −80° C.

[0126] Assay of the Telomerase Activity:

[0127] The inhibition of the telomerase activity is determined by aprotocol for extension of the oligonucleotide TS(^(5′)AATCGTTCGAGCAGAGTT^(3′)) (SEQ ID NO:2), in the presence of acellular extract enriched in telomerase activity and compounds which areadded at various concentrations (10, 1, 0.1 and 0.01 μg/ml). Theextension reaction is followed by a PCR amplification of the extensionproducts with the aid of the oligonucleotides TS and CXext(^(5′)GTGCCCTTACCCTTACCCTTACCCTAA^(3′)). (SEQ ID NO:3)

[0128] The reaction medium is prepared based on the followingcomposition: Tris HCl pH 8.3 20 mM MgCl2 1.5 mM Tween 20 0.005% (W/V)EGTA 1 mM DATP 50 μM DGTP 50 μM DCTP 50 μM DTTP 50 μM Oligonucleotide TS2 μg/ml Oligonucleotide CXext 2 μg/ml Bovine serum albumin 0.1 mg/ml TaqDNA polymerase 1 U/ml alpha 32P dCTP (3000 0.5 μl Ci/mmol) Telomeraseextract 200 ng in a volume of 10 μl Test product or solvent in a volumeof 5 μl Double distilled water QS 50 μl

[0129] The oligonucleotides are obtained from Eurogentec (Belgium) andare stored at −20° C. at a stock concentration of 1 mg/ml in distilledwater.

[0130] The reaction samples are assembled in 0.2 ml PCR tubes and onedrop of paraffin oil is deposited on each of the reactions of theexperiment before closing the tubes.

[0131] The reaction samples are then incubated in a Cetus 4800-type PCRapparatus under the following temperature conditions:

[0132] 15 minutes at 30° C.,

[0133] 1 minute at 90° C.,

[0134] followed by 30 cycle of,

[0135] 30 seconds at 94° C.,

[0136] 30 seconds at 50° C.,

[0137] and 1 minute 30 seconds at 72° C.,

[0138] followed by a final cycle of 2 minutes at 72° C.

[0139] For each of the samples, an aliquot of 10 μl is pipetted underthe oil layer and mixed with 5 μl of a loading buffer containing: TBE 3Xglycerol 32% (W/V) Bromophenol blue 0.03% Xylene cyanol 0.03%

[0140] The samples are then analyzed by electrophoresis on 12%acrylamide gel in a 1×TBE buffer for 1 hour at a voltage of 200 volts,with the aid of a Novex electrophoresis system.

[0141] The acrylamide gels are then dried on a sheet of whatmann 3MMpaper at 80° C. for 1 hour.

[0142] The analysis and the quantification of the reaction products arecarried out with the aid of an InstantImager apparatus (Pacard).

[0143] For each compound concentration tested, the results are expressedas percentage inhibition of the reaction and calculated from theuntreated enzymatic control and from the enzyme-free sample (blank)according to the following formula:

(Compound Value−blank value/enzymatic control value−blank value)×100.

[0144] The concentration of compound inducing a 50% inhibition of thetelomerase reaction (IC50) is determined with the aid of asemilogarithmic graphical representation of the inhibition valuesobtained as a function of each of the compound concentrations tested.

[0145] A compound is considered to be active as an antitelomerase agentwhen the quantity inhibiting 50% of the telomerase reaction is less than5 μM.

[0146] The Cytotoxic Biological Activity on Human Tumor Lines isDetermined According to the Following Experimental Protocol:

[0147] The human cell lines KB and A549 are obtained from ATCC (AmericanType Culture Collection, Rockville USA). The A549 cells are cultured ina layer in a culture flask in RPMI 1640 medium containing L-Glutamine at2 mM, Penicillin 200 U/ml, streptomycin 200 μg/ml and supplemented with10% heat-inactivated fetal calf serum. The KB cells are cultured in alayer in a culture flask in Dulbelco's medium containing L-Glutamine at2 mM, Penicillin 200 U/ml, streptomycin 200 μg/ml and supplemented with10% heat-inactivated fetal calf serum.

[0148] The cells at the exponential growth phase are trypsinized, washedin 1×PBS and are inoculated in 96-well microplates (Costar) in an amountof 4×10⁴ cells/ml for A549 and of 1.5×10⁴ cells/ml (0.2 ml/well) andthen incubated for 96 hours in the presence of variable concentrationsof product to be studied (10, 1, 0.1 and 0.01 μg/ml, each point inquadruplicate). 16 hours before the end of the incubation, 0.02% finalof neutral red is added to each well. At the end of the incubation, thecells are washed with 1×PBS and lysed with 1% sodium lauryl sulfate. Thecellular incorporation of the dye, which reflects cellular growth, isevaluated by spectrophotometry at a wavelength of 540 nm for each samplewith the aid of a Dynatech MR5000 reading apparatus.

[0149] For each compound concentration tested, the results are expressedas percentage inhibition of cellular growth and calculated from theuntreated control and the culture medium free of cells (blank) accordingto the following formula:

(Compound Value−blank value/cell control value−blank value)×100.

[0150] The concentration of compound inducing a 50% inhibition of growth(IC50) is determined with the aid of a semilogarithmic graphicalrepresentation of the inhibition values obtained as a function of eachof the compound concentrations tested.

[0151] A compound is considered to be active as cytotoxic agent if theconcentration inhibiting the growth of the tumor cells tested by 50% isin particular less than 10 μM.

[0152] The following and nonlimiting examples are given to illustratethe invention.

EXAMPLE 1 Parallel Synthesis of Substituted Derivatives ofN6-[6-Amino-4-Methylsulfanyl-[1,3,5]Triazin-2-yl]-2-Methylquinoline-4,6-Diamine

[0153]

[0154] Preparation ofN6-(6-Chloro-4-Methylsulfanyl-[1,3,5]Triazin-2-yl)-2-Methylquinoline-4,6-Diamine

[0155] 4.4 g (25 mmol) of 2-methylquinoline-4,6-diamine (which may beprepared according to J. Med. Chem., 35:252, 1992) and 2.8 g (25 mmol)of sodium carbonate are successively added, in a 1 litre three-neckedflask, to a solution of 5 g (25 mmol) of2,6-dichloro-6-methylsulfanyl-[1,3,5]triazine (which may be preparedaccording to J. Amer. Chem. Soc., 67:662, 1945), in 400 ml oftetrahydrofuran. The reaction mixture is heated under reflux for 16hours. After evaporation of the tetrahydrofuran, the residue is taken upin 400 ml of a mixture of water and dichloromethane (50-50 by volume).The organic phase is separated after settling out, dried over sodiumsulfate and concentrated to dryness under reduced pressure. 7.5 g (88%)ofN6-(6-chloro-4-methylsulfanyl-triazin-2-yl)-2-methylquinoline-4,6-diamineare then obtained, in the form of a pale yellow solid whosecharacteristics are the following:

[0156] melting point=294° C.

[0157]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 2.43 (s: 3H);2.52 (s: 3H); 6.47 (s: 1H); 6.61 (unresolved complex: 2H); 7.62 (broadd, J=9 Hz: 1H); 7.69 (d, J=9 Hz: 1H); 8.32 (unresolved complex: 1H);10.80 (unresolved complex: 1H).

Parallel Synthesis ofN6-[6-(2-Dimethylaminoethylamino)-4-Methylsulfanyl-[1,3,5]Triazin-2-yl]-2-Methylquinoline-4,6-Diamine(Example 1-1)

[0158] 50 mg (0.15 mmol) ofN6-(6-amino-4-methylsulfanyl-[1,3,5]triazin-2-yl)-2-methylquinoline-4,6-diamineare introduced into a heating magnetic reactor with a Zymark condenser,of the STEM RS2050 type, containing 25 wells in parallel each providedwith a 50 ml glass tube. 5 ml of dioxane, 16 mg (0.15 mmol) of sodiumcarbonate, 23 mg (0.15 mmol) of sodium iodide and 27 mg (0.3 mmol) of2-dimethylaminoethylamine are successively added to the first tube(Example 1-1). The reaction medium is heated by reflux and under argonfor 24 hours. After cooling, the content of the tube is evaporated underreduced pressure, taken up in 5 ml of water and 5 ml of ethyl acetateand filtered. The organic phase is separated by settling out, dried andconcentrated under reduced pressure. The crude product obtained is thenpurified by LC/MS using a Waters Xterra 3.5 μM C18 silica column 3 mm indiameter and 50 mm in length, eluting with a linear elution gradientconsisting, at the starting time (t₀=0 min), of water containing 0.05%trifluoroacetic acid and, at the final time (t_(f)=4 min), ofacetonitrile containing 0.05% trifluoroacetic acid. 58 mg ofN6-[(6-(methylquinolin-6-ylamino)-4-methylthiotriazin-2-yl]quinaldine-4,6-diaminetrifluoroacetate are thus obtained, after purification, whosecharacteristics are the following:

[0159] mass spectrum (DAD-TIC)=454 (MH⁺)

[0160] retention time=2.69 min (the retention times are obtained on ahypersil C 18 5 μm column 50 mm diameter 4.6 mm trade mark Purity Elite,eluting with a mixture of solvents A (H2O/TFA 0.05%) and B (ACN/TFA0.05%) with a linear gradient ranging from 95% A/5% B (t=0 min) to 10%A/90% B at t=3.5 min, then step 2 min).

[0161] Examples 1-1 to 1-26 were obtained by carrying out the procedureas above in a Zymark STEM RS2050 reactor. The structures, the variousoperating conditions used and the characteristics of Examples 1-1 to1-26 are summarized in the table below: Reaction conditionsCharacteristics No. of Retention Structure mmol of Mass time ExampleAlkN(R′3- Solvent Heating amine MH⁺ (min) 1-1

dioxane 17 h./100° 0.3 384 2.69 1-2

dioxane 17 h/100° 0.3 410 2.91 1-3

dioxane 17 h/100° 0 15 411 2.86 1-4

dioxane 3 d/100° 0.45 422 2.85 1-5

dioxane 17 h/100° 0.15 396 2.84 1-6

dioxane 17 h/100° 0.15 424 2.79 1-7

dioxane 17 h/100° 0.15 410 2 72 1-8

dioxane 2 d/100° 0.3 452 2.81 1-9

dioxane 10 ml/DMF1 % 24 h/100° 0.3 425 243 1-10

dioxane 10 ml/DMF1 % 24 h/100° 0.3 410 2 51 1-11

dioxane 10 ml/DMF1 % 24 h/100° 0 3 424 2.50 1-12

dioxane 10 ml/DMF1 % 24 h./100° 0.3 398 2 46 1-13

dioxane 10 ml/DMF1 % 24 h./100° 0 3 398 2 48 1-14

dioxane 10 ml/DMF1 % 24 h/100° 0.3 412 2 47 1-15

dioxane 10 ml/DMF1 % 24 h./100° 0.3 384 2.48 1-16

dioxane 10 ml/DMF1 % 24 h/100° 0 3 396 2.49 1-17

dioxane 10 ml/DMF1 % 24 h./100° 0.3 511 2 38 1-18

dioxane 10 ml/DMF1 % 24 h/100° 0.3 459 2.62 1-19

dioxane 10 ml/DMF1 % 24 h./100° 0.3 410 2.44 1-20

dioxane 10 ml/DMF1 % 24 h./100° 0.3 410 2.52 1-21

dioxane 10 ml/DMF1 % 24 h./100° 0.3 422 2 55 1-22

dioxane 10 ml/DMF1 % 24 h./100° 0.3 400 2.36 1-23

dioxane 10 ml/DMF1 % 24 h/100° 0.3 384 2.40 1-24

dioxane 10 ml/DMF1 % 24 h/100° 0.3 410 2.58 1-25

dioxane 10 ml/DMF1 % 24 h/100° 0.3 474 2.86

EXAMPLE 2 Parallel Synthesis of Substituted Derivatives ofN6-[6-Amino-4-Diethylamino-[1,3,5]Triazin-2-yl]-2-Methylquinoline-4,6-Diamine

[0162]

Preparation ofN6-(6-Chloro-4-Diethylamino-[1,3,5]Triazin-2-yl)-2-Methylquinoline-4,6-Diamine

[0163] 3.91 g (22.5 mmol) of 2-methylquinoline-4,6-diamine (which may beprepared according to J. Med. Chem. 35:252, 1992), and 2.4 g (22.5 mmol)of sodium carbonate are successively added, in a 1 litre three-neckedflask, to a solution of 5 g (22.5 mmol) of commercial2,6-dichloro-4-diethylamino-[1,3,5]triazine in 300 ml oftetrahydrofuran. The reaction mixture is heated to reflux for 20 hours.After evaporation of the tetrahydrofuran, the residue is taken up in 400ml of a mixture of water and dichloromethane (50-50 by volume). Theorganic phase is separated after settling out, dried over sodium sulfateand concentrated to dryness under reduced pressure. 7.4 g (92%) ofN6-(6-chloro-4-diethylaminotriazin-2-yl)-2-methylquinoline-4,6-diamineare thus obtained in the form of a yellow solid whose characteristicsare the following:

[0164] melting point=120° C.

[0165]¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.14 (mt: 6H);2.42 (s: 3H); from 3.50 to 3.70 (mt: 4H); 6.47 (s and unresolvedcomplex: 3H in total); 7.54 (broad d, J=9 Hz: 1H); 7.67 (dd, J=9 and 2Hz: 1H); 8.27 (unresolved complex: 1H); 10.09 (unresolved complex: 1H).

Parallel Synthesis ofN6-[(6-(3-Dimethylaminopropylamino)-4-Diethylamino-[1,3,5]Triazin-3-yl]-2-Methylquinoline-4,6-Diamine(Example 2-1)

[0166] 50 mg (0.13 mmol) ofN6-(6-chloro-4-diethylamino-[1,3,5]triazin-2-yl)-2-methylquinoline-4,6-diamineare introduced into a heating magnetic reactor with a Zymark condenser,of the STEM RS2050 type, containing 25 wells in parallel each providedwith a 50 ml glass tube. 5 ml of DMF, 19 mg (0.14 mmol) of potassiumcarbonate, 21 mg (0.14 mmol) of sodium iodide and 14 mg (0.14 mmol) of3-dimethylaminopropylamine are successively added to the first tube(Example 2-1). The reaction medium is heated at 120° C. under argon for16 hours. After cooling, the content of the tube is evaporated underreduced pressure and taken up in 5 ml of water, filtered and washed withdiethyl ether. The crude product obtained is then purified by LC/MSusing a Waters Xterra 3.5 μM C18 silica column 3 mm in diameter and 50mm in length, eluting with a linear elution gradient consisting, at thestarting time (t₀=0 min), of water containing 0.05% trifluoroacetic acidand, at the final time (t_(f)=4 min.), of acetonitrile containing 0.05%trifluoroacetic acid. 12 mg ofN6-[(6-(3-dimethylaminopropylamino)-4-diethylamino-[1,3,5]triazin-2-yl]-2-methylquinoline-4,6-diamineare thus obtained, after purification, whose characteristics are thefollowing:

[0167] mass spectrum (DAD-TIC)=423 (MH⁺)

[0168] retention time=0.79 min (the retention times are obtained on ahypersil C 18 5 μm column 50 mm diameter 4.6 mm trade mark Purity Elite,eluting with a mixture of solvents A (H2O/TFA 0.05%) and B (ACN/TFA0.05%) with a linear gradient ranging from 95% A/5% B (t=0 min) to 10%A/90% B at t=3.5 min, then step 2 min).

[0169] Examples 2-1 to 2-2 were obtained by carrying out the procedureas above in a Zymark STEM RS2050 reactor. The structures, the variousoperating conditions used and the characteristics of Examples 2-1 to 2-2are summarized in the table below: Reaction conditions CharacteristicsNo. of Retention Structure mmol of Mass time Example AlKN(R′3)- SolventHeating amine MH⁺ (min) 2-1

DMF 16 h./120° 0 14 423 0 79 2-2

DMF 16 h./120° 0.14 421 0.79 Table of biologica results TRAP G-4Cytotoxicity telomerase ΔTm A549 Example IC50 μM ° C. IC50 μM 1-1 0.79 61-2 0.5 5.6 7.5 1-3 4.4 3.1 1-4 0.1 5.6 1-5 1.6 2.8 1-6 1.36 1-7 0.471-8 0.98 8.5 1-9 1.64 7 1-10 0.94 7 1-11 1.1 4.5 1-12 3.1 1-13 2.9 1-143.2 1-15 4.6 1-16 1.29 1-17 1.6 1-19 1 1-20 3.1 1-21 0.7 1-22 3.2 1-233.8 1-24 3.9 1-25 1.5 10 1-26 0.86 33 <0.3 2-1 0.90 7.9 2-2 5.4 2.4

[0170]

1 3 1 21 DNA Artificial sequence oligonucleotide probe 1 gggttagggttagggttagg g 21 2 18 DNA Artificial sequence oligonucleotide probe 2aatcgttcga gcagagtt 18 3 27 DNA Artificial sequence oligonucleotideprobe 3 gtgcccttac ccttaccctt accctaa 27

We claim:
 1. A compound which binds the G-quadruplex structure of atelomere comprising the following general formula: nitrogen-containingaromatic ring —NR₃— distribution agent —NR′₃— nonaromatic hydrocarbonchain in which 1) the nitrogen-containing aromatic ring represents: a) aquinoline optionally substituted with at least i) a group N(Ra)(Rb) inwhich Ra and Rb, which are identical or different, represent hydrogen ora C1-C4 alkyl radical or ii) a group ORa in which Ra is as defined aboveb) a quinoline possessing a nitrogen atom in quaternary form or c) abenzamidine or d) a pyridine, 2) R3 and R′3, which are identical ordifferent, represent independently of each other, hydrogen or a C1-C4alkyl radical, 3) the distribution agent represents: a) a triazinegroup, a triazine group substituted with (i) an alkyl radical having 1to 4 carbon atoms, (ii) a thio radical, (iii) an oxy radical, or (iv) anamino radical, wherein the alkyl, thio, oxy or amino radicals areunsubstituted or substituted with i) one or more short-chain alkylgroups containing 1 to 4 carbon atoms or ii) a halogen atom or b) acarbonyl group or c) a group C(═NH)—NH—C(═NH) or d) an alkyldiyl groupcontaining 3 to 7 carbon atoms or e) a diazine group, a diazine groupsubstituted with (i) an alkyl radical having 1 to 4 carbon atoms, (ii) athio radical, (iii) an oxy radical, or (iv) an amino radical, whereinthe alkyl, thio, oxy or amino radicals are unsubstituted or substitutedwith i) one or more short-chain alkyl groups containing 1 to 4 carbonatoms or ii) a halogen atom, or a salt thereof.
 2. The compoundaccording to claim 1, wherein the distribution agent is a triazine ordiazine group.
 3. The compound according to claim 2, wherein the diazinegroup is a pyrimidine or quinazoline.
 4. The compound according to claim1, wherein the nonaromatic hydrocarbon chain is chosen from among i)alkyl (C1-C4), alkenyl (C2-C4), wherein the alkyl and alkenyl are linearor branched, ii) cycloalkyl (C3-C18) iii) cycloalkenyl (C3-C18) iv)heterocycloalkyl (C3-C18) and v) heterocycloalkyl (C3-C18) including thenitrogen atom of the NR′3 group.
 5. The compounds according to claim 4,wherein the nonaromatic hydrocarbon chain is unsubstituted orsubstituted with one or more atoms or radicals chosen from among halogenatoms, hydroxyl, aryl, heteroaryl, alkyloxy, aryloxy, thio, alkylthio,arylthio, amino, alkylamino, arylamino, dialkylamino, diarylamino,amidino, guanidino, alkylcarbonylamino, arylcarbonylamino, carboxyl,alkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyl arylcarbonyl,cyano, trifluoromethyl, and combinations thereof.
 6. The compoundsaccording to claim 5, wherein the alkyl chains comprise substituentshaving a hydrocarbon chain containing 1 to 4 carbon atoms, and the arylgroups comprise substituents having a hydrocarbon chain containing 5 to18 carbon atoms.
 7. The compounds according to claim 4, wherein thealkyl chains contain 2 to 3 carbon atoms, and the heterocycloalkyl orcycloalkyl chains contain 5 to 7 carbon atoms.
 8. The compoundsaccording to claim 1, comprising formula (I) below:

in which: 1) A represents: a) an amino group of formula NR1R2 in whichR1 and R2, which are identical or different, represent hydrogen or astraight or branched alkyl group containing 1 to 4 carbon atoms or b) agroup OR1 or SR1 in which R1 has the same meaning as above or c) analkyl group containing 1 to 4 carbon atoms or a trifluoromethyl group ord) a hydrogen atom or e) a halogen atom chosen from fluorine, chlorine,bromine and iodine, 2) R3 and R′3, which are identical or different,represent independently of each other hydrogen or a C1-C4 alkyl group,3) Ar₁ represents a nitrogen-containing aromatic ring representing: a) aquinoline, either unsubstituted or substituted with at least i) a groupN(Ra)(Rb) in which Ra and Rb, which are identical or different,represent hydrogen or a C1-C4 alkyl radical or ii) a group ORa in whichRa is as defined above b) a quinoline possessing a nitrogen atom inquaternary form or c) a benzamidine or d) a pyridine attached at the4-position or fused with an aryl or heteroaryl group e) a pyridineattached at the 4-position or fused with an aryl or heteroaryl groupsubstituted with a C1-C4 alkyl group, 4) alk represents a nonaromaticunsubstituted or substituted hydrocarbon chain chosen from among alkyl(C1-C4), alkenyl (C2-C4), wherein the alkyl and alkenyl chain are linearor branched, cycloalkyl (C3-C18), cycloalkenyl (C3-C18) heterocycloalkyl(C3-C18), and heterocycloalkyl (C3-C18) including the nitrogen atom ofthe NR′3 group, or a salt thereof.
 9. The compound according to claim 8,wherein the nonaromatic hydrocarbon chain is unsubstituted orsubstituted with one or more atoms or radicals chosen from among halogenatoms, hydroxyl, aryl, heteroaryl, alkyloxy, aryloxy, thio, alkylthio,arylthio, amino, alkylamino, arylamino, dialkylamino, diarylamino,amidino, guanidino, alkylcarbonylamino, arylcarbonylamino, carboxyl,alkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyl or arylcarbonyl,cyano, trifluoromethyl, and combinations thereof.
 10. Compoundsaccording to claim 8, wherein Ar₁ represents 4-amino- or 4-methylamino-or 4-dimethylamino-quinolyl or quinolinium, wherein the quinoliniumnucleus is unsubsituted or substituted with a methyl group. 11.Compounds according to claim 8, wherein group A represents a thiomethyl,amino, alkylamino or dialkylamino, in which the alkyl groups in theradicals possess 1 to 4 carbon atoms.
 12. Compounds according to claim8, wherein A represents a methylthio group.
 13. Compounds according toclaim 8, wherein alk represents an alkyl containing 2 to 3 linear orbranched carbon atoms, wherein the alkyl is substituted with i) anamino, alkylamino, arylamino, dialkylamino, diarylamino, or combinationthereof ii) an alkenyl unit containing 2 to 3 carbon atoms, which issubstituted with an amino, alkylamino arylamino, dialkylamino,diarylamino, heterocyclyl containing from 4 to 7 carbon atoms, or acombination thereof.
 14. Compounds according to claim 8, wherein alkrepresents a 2-(dialkylamino)ethyl, 3-(dialkylamino)propyl,2-(N-alkyl-N-arylamino)ethyl, or 3-(N-alkyl-N-arylamino)propyl, in whichthe alkyl groups contain 1 to 4 carbon atoms and the aryl groups contain5 to 18 carbon atoms.
 15. Compounds according to claim 8, wherein alkrepresents 2-(N-m.tolyl-N-ethylamino)ethyl.
 16. Compounds of claim 1,for use as a telomerase-inhibiting agent.
 17. Compounds of claim 1, foruse against cancer.
 18. Novel compounds corresponding to the followingformula (I):

in which: 1) A represents a) an amino group of formula NR1R2 in which R1and R2, which are identical or different, represent hydrogen or astraight or branched alkyl group containing 1 to 4 carbon atoms or b) agroup OR1 or SR1 in which R1 has the same meaning as above or c) analkyl group containing 1 to 4 carbon atoms or a trifluoromethyl group ord) a hydrogen atom or e) a halogen atom chosen from fluorine, chlorine,bromine and iodine, 2) R3 and R′3, which are identical or different,represent independently of each other hydrogen or a C1-C4 alkyl group,3) Ar₁ represents a nitrogen-containing aromatic ring representing: a) aquinoline, either unsubstituted or substituted with at least i) a groupN(Ra)(Rb) in which Ra and Rb, which are identical or different,represent hydrogen or a C1-C4 alkyl radical or ii) a group ORa in whichRa is as defined above b) a quinoline possessing a nitrogen atom inquaternary form or c) a benzamidine or d) a pyridine attached at the4-position or fused with an aryl or heteroaryl group e) a pyridineattached at the 4-position or fused with an aryl or heteroaryl groupsubstituted with a C1-C4 alkyl group, 4) alk represents a nonaromaticunsubstituted or substituted hydrocarbon chain chosen from among alkyl(C1-C4), alkenyl (C2-C4), wherein the alkyl and alkenyl chain are linearor branched, cycloalkyl (C3-C18), cycloalkenyl (C3-C18),heterocycloalkyl (C3-C18), and heterocycloalkyl (C3-C18) including thenitrogen atom of the NR′3 group, or a salt thereof.
 19. Compoundsaccording to claim 18, wherein the nonaromatic hydrocarbon chain isunsubstituted or substituted with one or more atoms or radicals chosenfrom among halogen atoms, hydroxyl, aryl, heteroaryl, alkyloxy, aryloxy,thio, alkylthio, arylthio, amino, alkylamino, arylamino, dialkylamino,diarylamino, amidino, guanidino, alkylcarbonylamino, arylcarbonylamino,carboxyl, alkyloxycarbonyl, aryloxycarbonyl, aminocarbonyl,alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl,alkylcarbonyl, arylcarbonyl, cyano, trifluoromethyl, and combinationsthereof.
 20. Compounds according to claim 18, wherein Ar₁ represents4-amino- or 4-methylamino- or 4-dimethylamino-quinolyl or quinolinium,wherein the quinolinium nucleus is unsubstituted or substituted with amethyl group.
 21. Compounds according to claim 18, wherein group Arepresents a thiomethyl, amino, alkylamino or dialkylamino, in which thealkyl groups in the radicals possess 1 to 4 carbon atoms.
 22. Compoundsaccording to claim 18, wherein R1 and R2 represent hydrogen. 23.Compounds according to claim 21, wherein A represents a methylthiogroup.
 24. Compounds according to claim 18, wherein alk represents i) analkyl containing 2 to 3 linear or branched carbon atoms which issubstituted with an amino, alkylamino, arylamino, dialkylamino,diarylamino, or combination thereof, ii) an alkenyl unit containing 2 to3 carbon atoms, which is substituted with an amino, alkylamino,arylamino, dialkylamino, diarylamino, or combination thereof, or iii) aheterocyclyl containing from 4 to 7 carbon atoms.
 25. Compoundsaccording to claim 18, wherein alk represents 2-(dialkylamino)ethyl,3-(dialkylamino)propyl, 2-(N-alkyl-N-arylamino)ethyl or3-(N-alkyl-N-arylamino)propyl, in which the alkyl groups contain 1 to 4carbon atoms and the aryl groups contain 5 to 18 carbon atoms. 26.Compounds according to claim 24, characterized in that alk represents a2-(N-m.tolyl-N-ethylamino)ethyl.
 27. A pharmaceutical product for humanuse comprising the compounds of claim
 1. 28. A therapeutic compositioncomprising a compound according to claim 1 and one or more anticancercompounds.
 29. The composition according to claim 28, wherein the one ormore anticancer compounds are chosen from among alkylating agents,platinum derivatives, antibiotic agents, antimicrotubule agents,anthracyclines, group I and II topoisomerases, fluoropyrimidines,cytidine analogs, adenosine analogs, L-asparaginase, hydroxyurea,transretinoic acid, suramine, irinotecan, topotecan, dexrazoxane,amifostine, herceptin, estrogenic hormones, and androgenic hormones. 30.A therapeutic combination comprising the compound according to claim 1and radiation.
 31. A method of using the composition of claim 29,wherein the individual compounds are administered to a patientsimultaneously separately or sequentially.